Rhesus monkeys are a crucial research resource, and major scientific advances in medicine, biology, and neuroscience can be attributed to their use. Despite recent strides in controlling colony diseases and enhancing the environment of captively housed primates, some monkeys develop a syndrome of self- injurious behavior (SIB). The occurrence of SIB compromises the goal of promoting psychological well-being as mandated by the Animal Welfare Act (Revised, 1991) and threatens the quality of the monkey research resource. During the previous grant period, we made significant strides in determining the underlying causes of SIB, in identifying factors that trigger episodes of SIB, in explaining why SIB persists, and in evaluating possible treatments. As a result of this effort, we have formulated an integrated developmental- neurochemical hypothesis in which SIB arises from adverse life events, is maintained by dysregulations of several neurochemical and physiological systems (e.g., the stress response system and the opioid system), and serves to reduce anxiety. Our goals during this next grant period are to test the generality of this hypothesis, develop screening procedures for identifying precursors to SIB in young primates, explore the influence of various candidate genes in the expression of SIB, and test efficacy of various therapies based directly on our research findings. In our first aim, we will test the hypothesis that SIB is associated with increased behavioral and physiological indices of anxiety. Specific Aim 2 will investigate the relationship between SIB and the endogenous opioid system and determine whether monkeys with SIB exhibit opioid receptor supersensitivity. The third specific aim will focus on a longitudinal prospective study of large cohort of monkeys to identify genetic, behavioral, and physiological markers of SIB. In Specific Aim 4, we will establish effective pharmacological treatments for SIB in monkeys and evaluate individual differences in treatment efficacy.